Type 2 diabetes mellitus (T2DM) is one of the most prevalent and serious metabolic disease characterized by an elevated level of blood glucose, affecting 6.4% of the world population and accounting for greater than 90% of diabetic patients.
Meanwhile, obesity is a major underlying pathology for the development of T2DM, non-alchoholic steatohepatitis (NASH) and cardiovascular disease. While insulin resistance is condition in which cells fail to utilize insulin properly, obesity is a central risk factor for the development of insulin resistance in the muscles, the fatty tissues and the liver of those having T2DM.
While an underlying mechanism for insulin resistance is still unclear, endoplasmic reticulum (ER) stress has been suggested as a new mechanism for the development of insulin resistance in obese individuals. ER stress can be caused by the disruption of Ca+2 homeostasis, overload of protein/lipid biosynthesis and oxidative stress, which then trigger an evolutionarily conserved mechanism referred to as the unfolded protein response (UPR) pathway including IRE1, ATF6 and PERK. Recently, it has been shown that ER stress and UPR pathway play a role in the pathogenesis of diabetes. However, the precise mechanism directly regulating the UPR pathway in diabetes is poorly understood.
In a mammalian liver, the members of the cytochrome P450 enzyme family (CYP450s) act mainly as ER membrane-localized NADPH monooxygenases responsible for catalyzing the oxidative metabolism of a wide variety of foreign chemicals and endogenous compounds. Under the conditions of obesity and diabetes, it has been reported that the expression profiles of CYP450s in the liver tissues are dynamic. In particular, CYP2E1 has been found to decrease the expression of ER chaperone proteins and induce ER protein damage and stress via its catalytic activation of pro-oxidants.